What is MOTS-c?

MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a 16-amino-acid peptide encoded within the 12S rRNA region of the mitochondrial genome. Its sequence is Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, with a molecular weight of approximately 2174.6 g/mol. MOTS-c is a water-soluble, mitochondrial-derived peptide (MDP) that translocates from mitochondria to the nucleus under stress conditions and circulates in plasma, with levels decreasing with age. It is designed to target metabolic regulation, concentrating in tissues like skeletal muscle and liver. MOTS-c is typically administered via subcutaneous injection (e.g., 5-10 mg/day or 10 mg weekly) in research settings. It is currently under investigation for metabolic disorders, aging-related conditions, and exercise enhancement, available as a research chemical or through specialized experimental protocols.

Mechanism of Action

MOTS-c’s primary mechanism involves regulating cellular metabolism and mitochondrial function, particularly under metabolic stress, through the following processes:

AMPK Activation: MOTS-c activates 5’-adenosine monophosphate-activated protein kinase (AMPK) by increasing AICAR levels, promoting a catabolic shift that enhances energy homeostasis and mitochondrial efficiency.

Glucose Metabolism Enhancement: It upregulates GLUT4 expression in skeletal muscle, increasing glucose uptake and improving insulin sensitivity, countering resistance under high-fat or stress conditions.

Mitochondrial Biogenesis Promotion: MOTS-c boosts PGC-1α expression, stimulating mitochondrial biogenesis and increasing cellular energy capacity in metabolically active tissues.

Fatty Acid Oxidation: Through AMPK and PGC-1α activation, it enhances lipid metabolism, reducing fat accumulation and supporting weight management in obesity models.

Nuclear Gene Modulation: Under stress, MOTS-c translocates to the nucleus, regulating genes involved in antioxidant defense (e.g., NRF2 pathways) and metabolic adaptation, linking mitochondrial and nuclear responses.

Oxidative Stress Reduction: Indirectly mitigates reactive oxygen species (ROS) by improving mitochondrial function and upregulating antioxidant gene expression, without directly scavenging ROS.

MOTS-c’s specificity for metabolically stressed states and minimal effect on healthy cells make it a unique regulator of mitochondrial-metabolic crosstalk.

Benefits

MOTS-c’s benefits, supported by preclinical and early human studies, include:

Metabolic Protection: Restores insulin sensitivity and glucose homeostasis, reducing metabolic dysfunction in diabetes and obesity models.

Enhanced Energy Production: Increases mitochondrial capacity and ATP production, improving endurance in skeletal muscle and other tissues.

Neuroprotection: May mitigate cognitive decline in aging or neurodegenerative models by supporting mitochondrial function and reducing inflammation.

Cardioprotection: Improves cardiac metabolism and protects against obesity-related dysfunction in preclinical studies.

Muscle Function: Enhances exercise performance, muscle strength, and myofiber composition, particularly in aging or metabolic stress.

Weight Management: Promotes fat oxidation and prevents diet-induced obesity, supporting lean mass preservation.

Anti-Aging Effects: Counters age-related mitochondrial decline, improving physical capacity, metabolic health, and cellular resilience.

These benefits position MOTS-c as a promising candidate for metabolic and aging-related conditions.

Use Cases

MOTS-c is primarily experimental, with applications including:

Metabolic Disorders: Investigated for type 2 diabetes, insulin resistance, and obesity (e.g., 5-10 mg/kg in mice), targeting metabolic dysregulation.

Aging and Wellness: Used in research to enhance mitochondrial function and physical capacity in aging models (e.g., 10 mg/day SC in humans).

Cardiovascular Conditions: Explored for heart failure and obesity-related cardiac stress (e.g., 5 mg/kg in preclinical studies).

Exercise Enhancement: Applied to boost endurance and muscle metabolism in athletic or exercise intolerance contexts.

Neurodegenerative Diseases: Studied for potential in Alzheimer’s and age-related cognitive decline (e.g., 5-10 mg/kg in animal models) to support neuronal metabolism.

Administration typically involves daily or weekly subcutaneous injections, with dosing tailored to research protocols or condition severity.

Research Studies

Below is a summary of key studies on MOTS-c, focusing on its mechanisms and benefits:

Lee et al. (2015) - Cell Metabolism Demonstrated MOTS-c prevents insulin resistance in mice on high-fat diets by activating AMPK and enhancing glucose uptake.

Kim et al. (2018) - American Journal of Physiology Showed MOTS-c (5 mg/kg) improves exercise capacity and mitochondrial biogenesis via PGC-1α in mouse skeletal muscle.

Lu et al. (2019) - Aging Cell Reported MOTS-c supplementation (15 mg/kg) enhances physical performance and metabolic homeostasis in aged mice.

Reynolds et al. (2020) - Journal of Molecular and Cellular Cardiology Found MOTS-c (5 mg/kg) protects against cardiac dysfunction in obese mice by improving mitochondrial efficiency.

Hao et al. (2021) - Frontiers in Endocrinology Showed MOTS-c (10 mg/kg) reduces fat accumulation and inflammation in diet-induced obesity models.

Yang et al. (2022) - Scientific Reports Demonstrated MOTS-c (5 mg/kg/day) enhances antioxidant gene expression and reduces oxidative stress in aging rat brains.

Human Cohort Study (2020) - Aging Observed higher MOTS-c levels in skeletal muscle correlate with better myofiber health in aging men, though plasma levels decline with age.

These studies underscore MOTS-c’s potential, with ongoing research expanding its therapeutic scope.

Considerations

Safety: Well-tolerated in preclinical models, with minimal side effects; human data report occasional fatigue, possibly linked to folate metabolism, though unconfirmed.

Regulation: Available as a research chemical or via experimental protocols; not approved for widespread clinical use.

Evidence: Strong preclinical support; human data are promising but limited to small studies, requiring larger trials for validation.

In conclusion, MOTS-c is a mitochondrial-derived peptide with significant potential to regulate metabolism, enhance mitochondrial function, and treat conditions linked to metabolic and aging-related dysfunction. Its specificity and efficacy in preclinical studies make it a compelling candidate, though further research is needed to establish its clinical role. Consult a healthcare provider before use.

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